Salinomycin derivatives and therapeutic uses thereof

Abstract

The invention relates to salinomycin derivatives such as compounds having the structure of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a therapeutically effective amount of compounds of formula (I), and the use of compounds of formula (I) for treating or inhibiting progression of cancer. The cancer is selected from the group consisting of breast cancer, pancreatic cancer, and prostate cancer.

What is claimed is: 
     
       1. A compound having the structure of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is 
       
       
         
           
           
               
               
           
         
         R is selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 7  carbocyclyl, 5-10 membered heterocyclyl, C 6-10  aryl, and 5-10 membered heteroaryl; 
         n is an integer from 0 to 6; 
         Y is selected from the group consisting of —NR 1 C(O), —C(O)NR 1 —, —OC(O)—, C(O)O—, —CR 1 (COOR 2 )—CR 3 ═CR 4 —, and —CR 1 ═CR 2 —; 
         m is an integer from 0 to 6; 
         Z is —CR 1 ═CR 2 —, —CR 1 (COOR 2 )—CR 3 ═CR 4 , or absent; 
         G is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 7  carbocyclyl, 5-10 membered heterocyclyl, C 6-10  aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4  alkyl, halogenC 1-4  alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; and 
         each of R 1 , R 2 , R 3 , R 4 , and R 5  are independently selected from —H, —CN, —NO 2 , —NH 2 , —OH, C 1-4  alkyl, halogenC 1-4  alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7  cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl. 
       
     
     
       2. The compound of  claim 1 , wherein R is H or CH 3 . 
     
     
       3. The compound of  claim 1 , wherein n is 0, 2, or 4. 
     
     
       4. The compound of  claim 1 , wherein Y is —NR 1 C(O), —C(O)NR 1 —, —OC(O)—, or C(O)O—. 
     
     
       5. The compound of  claim 4 , wherein R 1  is H. 
     
     
       6. The compound of  claim 1 , wherein Y is —CR 1 ═CR 2 —. 
     
     
       7. The compound of  claim 6 , wherein R 1  is CN and R 2  is H. 
     
     
       8. The compound of  claim 1 , wherein Y is —CR 1 (COOR 2 )—CR 3 ═CR 4 —. 
     
     
       9. The compound of  claim 8 , wherein R 1 , R 3 , and R 4  are H, and R 2  is CH 3 . 
     
     
       10. The compound of  claim 1 , wherein m is 0, 1, or 3. 
     
     
       11. The compound of  claim 1 , wherein Z is —CR 1 ═CR 2 —. 
     
     
       12. The compound of  claim 11 , wherein each of R 1  and R 2  are independently H or CN. 
     
     
       13. The compound of  claim 12 , wherein Z is C(CN)═CH. 
     
     
       14. The compound of  claim 1 , wherein Z is —CR 1 (COOR 2 )—CR 3 ═CR 4 . 
     
     
       15. The compound of  claim 14 , wherein each of R 1 , R 2 , R 3 , and R 4  are H or C 1-4  alkyl. 
     
     
       16. The compound of  claim 15 , wherein R 1 , R 3 , and R 4  are H, and R 2  is CH 3 . 
     
     
       17. The compound of  claim 1 , wherein Z is absent. 
     
     
       18. The compound of  claim 1 , wherein G is C 6-10  aryl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4  alkyl, halogenC 1-4  alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 . 
     
     
       19. The compound of  claim 18 , wherein G is a phenyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4  alkyl, halogenC 1-4  alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 . 
     
     
       20. The compound of  claim 19 , wherein G is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
       21. The compound of  claim 1 , wherein G is 5-10 membered heteroaryl optionally substituted with 0-3 substituents selected from the group consisting of halogen, C 1-4  alkyl, halogenC 1-4  alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 . 
     
     
       22. The compound of  claim 21 , wherein G is selected from imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted with halogen, C 1-4  alkyl, halogenC 1-4  alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 . 
     
     
       23. The compound of  claim 21 , wherein G is pyridine. 
     
     
       24. The compound of  claim 1 , having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
       25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient.